Abstract
Natural killer (NK) cells are immune innate effectors playing a pivotal role in the immunosurveillance of multiple myeloma (MM) since they are able to directly recognize and kill MM cells. In this regard, among activating receptors expressed by NK cells, NKG2D represents an important receptor for the recognition of MM cells, being its ligands expressed by tumor cells, and being able to trigger NK cell cytotoxicity. The MHC class I-related molecule A (MICA) is one of the NKG2D ligands; it is encoded by highly polymorphic genes and exists as membrane-bound and soluble isoforms. Soluble MICA (sMICA) is overexpressed in the serum of MM patients, and its levels correlate with tumor progression. Interestingly, a methionine (Met) to valine (Val) substitution at position 129 of the α2 heavy chain domain classifies the MICA alleles into strong (MICA-129Met) and weak (MICA-129Val) binders to NKG2D receptor. We addressed whether the genetic polymorphisms in the MICA-129 alleles could affect MICA release during MM progression. The frequencies of Val/Val, Val/Met, and Met/Met MICA-129 genotypes in a cohort of 137 MM patients were 36, 43, and 22%, respectively. Interestingly, patients characterized by a Val/Val genotype exhibited the highest levels of sMICA in the sera. In addition, analysis of the frequencies of MICA-129 genotypes among different MM disease states revealed that Val/Val patients had a significant higher frequency of relapse. Interestingly, NKG2D was downmodulated in NK cells derived from MICA-129Met/Met MM patients. Results obtained by structural modeling analysis suggested that the Met to Val dimorphism could affect the capacity of MICA to form an optimal template for NKG2D recognition. In conclusion, our findings indicate that the MICA-129Val/Val variant is associated with significantly higher levels of sMICA and the progression of MM, strongly suggesting that the usage of soluble MICA as prognostic marker has to be definitely combined with the patient MICA genotype.
Highlights
Natural killer (NK) cells represent innate immune effectors playing a pivotal role in tumor surveillance
Our findings indicate that the MICA-129Met/Val dimorphism is associated with: (i) differential expression of both soluble and cell-surface MICA, (ii) expression levels of NK group 2D (NKG2D) on ex vivo NK cells isolated from the bone marrow (BM) and peripheral blood (PBL) of MM patients, and (iii) the disease state
We investigated whether soluble NKG2D ligands other than MICA in the sera derived from a cohort of MM patients at different disease states, namely MGUS, smoldering, onset, and relapse, were associated with MM progression
Summary
Natural killer (NK) cells represent innate immune effectors playing a pivotal role in tumor surveillance. Recognition of abnormal self on tumor cells triggers a number of non-MHC class I-restricted activating receptors, such as NK group 2D (NKG2D), DNAX accessory molecule-1 (CD226), and the natural cytotoxicity receptors [1]. NKG2D recognizes two families of ligands in humans: the MHC class I chain-related protein A/B (MICA/B) and the UL16-binding proteins (ULBP16) [1]. Among all known NKG2D ligands, MICA is the most polymorphic non classical class I gene, with 104 alleles identified to date (http://www.ebi.ac.uk/imgt/hla/, release 3.25.0). The singlenucleotide polymorphism causing a valine (Val) to methionine (Met) modification at position 129 of the α2 heavy chain domain classifies these MICA alleles into high-affinity (MICA-129Met) and low-affinity (MICA-129Val) binders to NKG2D receptor [5]. Significant differences in binding affinities of MICA alleles for NKG2D could have different effects on NK cell activation, in particular under conditions of suboptimal MICA expression
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